Dexamethasone Downregulates Calcification-Inhibitor Molecules and Accelerates Osteogenic Differentiation of Vascular Pericytes: Implications for Vascular Calcification

• Published in: Circulation research Vol. 98; no. 10; pp. 1264 - 1272
• Main Authors: Kirton, John Paul, Wilkinson, Fiona L, Canfield, Ann E, Alexander, M Yvonne
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 26.05.2006; Lippincott
• Subjects: Animals; Biological and medical sciences; Calcinosis - etiology; Calcinosis - prevention & control; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cattle; Cell Differentiation - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Dexamethasone - pharmacology; Down-Regulation; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Genes - drug effects; Genes - physiology; Glucocorticoids - pharmacology; Matrix Gla Protein; Minerals - metabolism; NF-kappa B - antagonists & inhibitors; Osteogenesis; Osteopontin; Pericytes - cytology; Pericytes - metabolism; Proteins - genetics; Proteins - metabolism; Retina - cytology; RNA, Messenger - metabolism; Sialoglycoproteins - genetics; Sialoglycoproteins - metabolism; Vascular Diseases - etiology; Vertebrates: cardiovascular system; Corticosteroid; Pericyte; Dexamethasone; Steroid hormone; pericytes; Glucocorticoid; Vertebrata; Mammalia; Gene; gene regulation; Calcification; Inhibitor; Circulatory system; Differentiation
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000223056.68892.8b

Vascular calcification is present in many pathological conditions and is recognized as a strong predictor of future cardiovascular events. Current evidence suggests that it is a regulated process involving inducing and inhibitory molecules. Glucocorticoids have great clinical importance as antiinflammatory drugs and can act as potent inducers of osteogenic differentiation in vitro. The effect of glucocorticoids on vascular cells in vivo remains obscure. Pericytes are pluripotent cells that can differentiate into osteoblasts, and recent evidence suggests that they could participate in vascular calcification. We hypothesized that the synthetic glucocorticoid dexamethasone would enhance the rate of pericyte differentiation and mineralization in vitro with a concomitant suppression of calcification-inhibitory molecules. Three weeks of dexamethasone treatment induced a 2-fold increase in (1) alkaline phosphatase activity, (2) calcium deposition, and (3) the number of nodules formed in vitro; and a reduction in the expression of matrix Gla protein (MGP), osteopontin (OPN), and vascular calcification-associated factor (VCAF) mRNAs. The glucocorticoid receptor antagonist Org 34116 abolished dexamethasone-accelerated pericyte differentiation, nodule formation, and mineralization. Data obtained using Org 34116, the transcription inhibitor actinomycin D, and the protein synthesis inhibitor cyclohexamide suggest that MGP, OPN, and VCAF mRNA abundance are controlled at different and multiple levels by dexamethasone. This is the first report showing that dexamethasone enhances the osteogenic differentiation of pericytes and downregulates genes associated with inhibition of mineralization. Our study highlights the need for further investigation into the long-term consequences of prolonged glucocorticoid therapy on vascular calcification.